Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission

Herbeck, Joshua T.; Müller, Viktor; Maust, Brandon S.; Ledergerber, Bruno; Torti, Carlo; Giambenedetto, Simona Di; Gras, Luuk; Günthard, Huldrych F.; Jacobson, Lisa P.; Mullins, James I.; Gottlieb, Geoffrey S.

doi:10.1097/qad.0b013e32834db418

Cited by 81 publications

(110 citation statements)

References 69 publications

(80 reference statements)

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“…Despite this, a pattern appears to be emerging. While studies undertaken prior to the mid-1990s yielded conflicting results (72)(73)(74)(75)(76), more recent reports support the observation that HIV may be increasing in virulence as the epidemic progresses (77)(78)(79)(80)(81)(82)(83)(84)(85).…”

Section: Discussionmentioning

confidence: 87%

Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Nomura

Hosoya

Brumme

et al. 2013

J Virol

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f Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasmaderived gag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4 ؉ T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wildtype NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

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Section: Discussionmentioning

confidence: 87%

Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Nomura

Hosoya

Brumme

et al. 2013

J Virol

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“…Although the predictions of these models are conflicting, the available data are also conflicting. Average SPVL has increased in some populations and decreased in others since the introduction of ART (Herbeck et al., 2012). As different populations are likely to experience different selection pressures, understanding the role and relative influence of those potential pressures is important.…”

Section: Introductionmentioning

confidence: 99%

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Mideo

2017

Evolutionary Applications

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Average HIV‐1 virulence appears to have evolved in different directions in different host populations since antiretroviral therapy first became available, and models predict that HIV drugs can select for either higher or lower virulence, depending on how treatment is administered. However, HIV virulence evolution in response to “leaky” therapy (treatment that imperfectly suppresses viral replication) and the use of preventive drugs (pre‐exposure prophylaxis) has not been explored. Using adaptive dynamics, we show that higher virulence can evolve when antiretroviral therapy is imperfectly effective and that this evolution erodes some of the long‐term clinical and epidemiological benefits of HIV treatment. The introduction of pre‐exposure prophylaxis greatly reduces infection prevalence, but can further amplify virulence evolution when it, too, is leaky. Increasing the uptake rate of these imperfect interventions increases selection for higher virulence and can lead to counterintuitive increases in infection prevalence in some scenarios. Although populations almost always fare better with access to interventions than without, untreated individuals could experience particularly poor clinical outcomes when virulence evolves. These findings predict that antiretroviral drugs may have underappreciated evolutionary consequences, but that maximizing drug efficacy can prevent this evolutionary response. We suggest that HIV virulence evolution should be closely monitored as access to interventions continues to improve.

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“…Recent studies have shown a trend of increasing set-point VLs over the last 30 years of the HIV-1 epidemic (7,8), raising the possibility of both increasing transmission rates and virulence in treatment of naïve HIV-1 infection. A plausible explanation for this observation is viral adaptation to the host at the population level over time (9,10), providing a further challenge for HIV-1 vaccine design.…”

mentioning

confidence: 99%

Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

Yue

Prentice

Farmer

et al. 2013

J Virol

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fIn HIV-1 infection, the early set-point viral load strongly predicts both viral transmission and disease progression. The factors responsible for the wide spectrum of set-point viral loads are complex and likely reflect an interplay between the transmitted virus and genetically defined factors in both the transmitting source partner and the seroconverter. Indeed, analysis of 195 transmission pairs from Lusaka, Zambia, revealed that the viral loads in transmitting source partners contributed only ϳ2% of the variance in early set-point viral loads of seroconverters (P ‫؍‬ 0.046 by univariable analysis). In multivariable models, early setpoint viral loads in seroconverting partners were a complex function of (i) the viral load in the source partner, (ii) the gender of the seroconverter, (iii) specific HLA class I alleles in the newly infected partner, and (iv) sharing of HLA-I alleles between partners in a transmission pair. Each of these factors significantly and independently contributed to the set-point viral load in the newly infected partner, accounting for up to 37% of the variance observed and suggesting that many factors operate in concert to define the early virological phenotype in HIV-1 infection. The HIV-1 set-point viral load (VL) in infected individuals directly affects the transmission rate of the virus (1-3) and early disease progression (4-6). Recent studies have shown a trend of increasing set-point VLs over the last 30 years of the HIV-1 epidemic (7, 8), raising the possibility of both increasing transmission rates and virulence in treatment of naïve HIV-1 infection. A plausible explanation for this observation is viral adaptation to the host at the population level over time (9, 10), providing a further challenge for HIV-1 vaccine design. The determinants of set-point VL in newly infected individuals include viral genetic factors (11-13) and host genetic factors (14-16). Thus, to comprehensively define the role of underlying factors in determining early set-point VL, it is necessary to understand the complexity of the interaction between the transmitted founder virus, with its embedded footprints of the immune response of the transmitting source partner (TSP), and the de novo immune defense of the seroconverting partner (SC).We previously observed that cytotoxic T-lymphocyte (CTL) epitope escape mutations selected by immune pressure in the TSP can modulate the early set-point VL in the SC (11, 17), suggesting that mutations that would be expected to positively impact VL in the TSP can negatively impact VL in the seroconverter. This observation is consistent with our previous studies of the ZEHRP cohort and with other studies of heterosexual cohorts of limited size. These studies demonstrated a relatively weak correlation between VLs in TSPs and SCs in linked heterosexual transmission partners (18)(19)(20). In contrast, a more significant VL correlation was shown for a transmission pair cohort of men who have sex with men (MSM) in San Francisco (21), and a phylogenetic analysis of MSM in the Swi...

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Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission

Cited by 81 publications

References 69 publications

Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

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